The present invention relates to novel processes for the preparation of 13-ether derivatives of milbemycins, and to novel intermediates for use in such processes.
There are several classes of known compounds with a structure based on a 16-membered macrolide ring, which compounds are obtained by fermentation of various microorganisms or are obtained semi-synthetically by chemical derivatization of such natural fermentation products, and which exhibit acaricidal, insecticidal, anthelmintic and antiparasitic activities. The milbemycins are one such class.
In order to avoid confusion, a standardized system of nomenclature for the milbemycins will be used herein, which follows the normal rules for naming derivatives of organic compounds as recommended by the International Union of Pure and Applied Chemistry, Organic Chemistry Division, Commission on Nomenclature of Organic Chemistry, and which is based primarily on the hypothetical parent compound hereby defined as "milbemycin" and represented by the formula (A): ##STR2##
For the avoidance of doubt, formula (A) also shows the numbering of positions of the macrolide ring system applied to those positions most relevant to the compounds of the present invention and of the prior art.
The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, acaricidal and insecticidal activities. Milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as "Compound B-41D", and milbemycins A.sub.3 and A.sub.4 were disclosed in U.S. Pat. No. 3,950,360. These compounds may be represented by the above formula (A) in which there is a hydrogen atom at position 13 and position 25 is substituted with a methyl group, an ethyl group or an isopropyl group, these compounds being designated as milbemycin a.sub.3, milbemycin A.sub.4 and milbemycin D, respectively.
13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat. No. 4,423,209, and milbemycin 5-oxime derivatives have been disclosed in U.S. Pat. No. 4,547,520 and in European Patent Publication No. 203 832.
Milbemycins having an ether group at the 13-position have been found to have various useful activities, including particularly strong anthelmintic activity in cattle, for example. The nature of the ether group is not particularly important but it is generally an alkoxy, alkenyloxy, alkynyloxy or aralkoxy group, the substituted phenylalkoxy groups, particularly the phenethoxy group, being most preferred. For example, European Patent Publication No. 357 460 discloses milbemycin derivatives having an optionally substituted phenethoxy group at the 13-position, these compounds having excellent anthelmintic activity.
However, the problem with the 13-ether substituted milbemycins is that there is no commercially viable process for their production. The processes which are described for the production of these compounds in the prior art necessarily employ toxic and/or expensive metal catalysts.
The prior art processes essentially fall into two categories, and the two types of prior art process which are generally used in the manufacture of 13-ether substituted milbemycins involve either:
1) Reacting a milbemycin having a leaving group, such as iodine, in the 13-position with an appropriate alcohol in the presence of a catalyst; or PA1 2) Reacting a 15-hydroxy substituted milbemycin derivative with an appropriate alcohol in the presence of an acid. PA1 to give a compound of formula (II): ##STR7## wherein R and R.sup.5 are as defined above; PA1 C. reacting the resulting compound of formula (III) with a compound of formula R.sup.1O OH to give said compound of formula (VIIa). PA1 R.sup.11 and R.sup.12 are independently selected from the group consisting of: hydrogen atoms; halogen atoms; cyano groups; nitro groups; C.sub.1 -C.sub.4 alkyl groups; substituted C.sub.1 -C.sub.4 alkyl groups having at least one substituent selected from the group consisting of substituents (a), defined below; C.sub.1 -C.sub.4 alkoxy groups; C.sub.2 -C.sub.6 alkoxyalkoxy groups; groups of formula --(CH.sub.2).sub.n NHR.sup.19, PA1 in which: n represents 0 or the integer 1 or 2, and R.sup.19 represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group; PA1 in which: PA1 in which n, R.sup.16 and R.sup.19 are as defined above; PA1 in which n and R.sup.19 are as defined above and R.sup.17 represents a C.sub.1 -C.sub.4 alkyl group, a C.sub.3 -C.sub.8 cycloalkyl group or an aralkyl group as defined below; PA1 in which n, R.sup.16 and R.sup.19 are as defined above; PA1 in which n, R.sup.16 and R.sup.19 are as defined above; PA1 in which n, R.sup.16 R.sup.17 and R.sup.19 are as defined above; PA1 in which n, R.sup.16 and R.sup.19 are as defined above and the two symbols Y are independently selected from the group consisting of oxygen and sulfur atoms; PA1 in which n, Y and R are as defined above, and the two symbols R.sup.16 are independently selected from the group consisting of R.sup.16 or the two together with the nitrogen atom to which they are attached, form a heterocyclic group having from 3 to 7 ring atoms of which one is said nitrogen atom and 0 or 1 is an additional hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms; PA1 in Which n, Y and R.sup.19 are as defined above, and each of the symbols R.sup.16" is independently selected from the group consisting of R.sup.16 or any two of the symbols R.sup.16" together with the nitrogen atom to which each is attached, forms a heterocyclic group having from 3 to 7 ring atoms of which one or two is said nitrogen atom or atoms and 0 or 1 is an additional hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms; PA1 in which n, Y, R.sup.16 and R.sup.19 are as defined above and Z represents PA1 in which n and R.sup.19 are as defined above and the two symbols R.sup.20 are independently selected from the group consisting of R.sup.16 cyano groups, nitro groups, groups of formula --COOR.sup.17 in which R.sup.17 is as defined above, and groups of formula --COR.sup.16, in which R.sup.16 is as defined above; PA1 in which n, R.sup.16, R.sup.19 and R.sup.20 are as defined above; PA1 in which n, R.sup.16 and R.sup.19 are as defined above and m is 1 or 2; PA1 in which R.sup.16 is as defined above; and PA1 in which R.sup.17 is as defined above; PA1 halogen atoms, C.sub.1 -C.sub.4 alkoxy groups, C.sub.1 -C.sub.4 alkylthio groups and C.sub.1 -C.sub.5 alkanoyloxy groups; PA1 C.sub.3 -C.sub.8 cycloalkyl groups; C.sub.1 -C.sub.4 alkoxy groups; C.sub.1 -C.sub.4 alkylthio groups; C.sub.2 -C.sub.5 cyanoalkylthio groups; C.sub.2 -C.sub.5 alkoxycarbonyl groups; halogen atoms; cyano groups; nitro groups; amino groups; carbocyclic aryl groups having from 6 to 10 carbon atoms and being unsubstituted or having at least one substituent selected from the group consisting of substituents (c), defined below; aromatic heterocyclic groups having from 5 to 8 ring atoms of which from 1 to 4 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, said heterocyclic group being monocyclic or fused either to a benzene ring or to a heterocyclic group which has 5 or 6 ring atoms of which from 1 to 3 are nitrogen hetero-atoms and being unsubstituted or having at least one substituent selected from the group consisting of substituents (c), defined below; and aryloxy and arylthio groups in which the aryl part has from 6 to 10 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (c), defined below; PA1 C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, PA1 C.sub.1 -C.sub.4 alkylthio groups, C.sub.1 -C.sub.5 alkanoyloxy groups, C.sub.2 -C.sub.5 alkoxycarbonyl groups, halogen atoms, cyano groups, nitro groups, amino groups, mono- and di-alkylamino groups in which the or each alkyl part is C.sub.1 -C4, carbamoyl groups, mono- and di-alkylcarbamoyl groups in which the or each alkyl part is C.sub.1 -C.sub.4, and C.sub.1 -C.sub.5 alkanoylamino groups;
In the case of 1) above, a suitable process is described in Japanese Unexamined Patent Publication No. Hei-2-174780, corresponding to European Patent Publication No. 357 460.
In the case of 2) above, a suitable process is described in Japanese Unexamined Patent Publication No. Sho-61-178986, corresponding to US Patent No. 4,696,945.
With regard to process 1), the catalysts employed are the oxides or salts of silver or mercury. Silver catalysts are very expensive to use in bulk manufacturing operations, even when it is possible to recover the catalyst from the final product. On the other hand, mercury is toxic, and care must be exercised to ensure that all mercury is removed from the final product.
With regard to process 2), there are two main problems. The first problem lies in the reaction of the 15-hydroxy compound with the alcohol. The reaction scheme with partial formulae is as shown below: ##STR3## It can be seen that the reaction of the 15-hydroxy compound of partial structure (a) with alcohol yields a mixture of products (b) and (c). In addition, the starting compound must also be protected at the 5-hydroxy position before the reaction can be performed.
The second, more serious problem, with process 2) is concerns the manufacture of the starting material (a). Japanese Unexamined Patent Publication No. Sho 60-158191, (corresponding to European Patent Publication No. 147852), and Helvetica Chimica Acta, 73, 1905 (1990), describe a process wherein the 15-hydroxy compound (a) can be obtained by treating a 14,15-epoxy compound (d) with a mixture of hydrogen azide and triethylaluminum. The reaction scheme with partial formulae is as follows: ##STR4##
From the above reaction scheme, it can be seen that the compound of formula (a) is obtained together with the 14-azide compound (e). The hydrogen azide used in this process is highly toxic and dangerous (Shin-Jikken Kagaku Kouza, 8, pp. 327 and 328, Compiled by Japan Chemical Association, published by Maruzen, Dec. 20, 1976). Triethyl aluminum is also dangerous, because it ignites when brought into contact with water or air, even at room temperature (Shin-Jikken Kagaku Koza, 12, p. 308, compiled by Japan Chemical Association, published by Maruzen, issued on Mar. 20, 1976). Furthermore, as is well known with dry azide compounds (Shin-Jikken Kagaku Koza, 14, p. 1660, compiled by Japan Chemical Association, published by Maruzen, Feb. 20, 1978), there is a danger of the 14-azide compound (e) exploding if exposed to heat or mechanical shock. Thus, the known method for preparing the starting material of formula (a) is not only impractical but also dangerous for bulk manufacturing operations.
Japanese Patent Application No. Hei-3-258036, published in May 1993, discloses a process for preparing 13-substituted milbemycin derivatives starting from a 5-hydroxy milbemycin compound.